(1) Field of the Invention
There is provided useful drugs and pro-drugs that are N.sup.6 heterocyclic 8 modified adenosine derivatives. The compositions of this invention are selective, partial or full adenosine A.sub.1 receptor agonists, and as such, are useful for modifying cardiac activity, modifying adipocyte function, treating central nervous system disorders, and treating diabetic disorders and obesity in mammals, and especially in humans.
(2) Description of the Art
There are at least two subtypes of adenosine receptors in the heart: A.sub.1 and A.sub.2A. Each subtype affects different physiological functions. The A.sub.1 adenosine receptor mediates two distinct physiological responses. Inhibition of the cardiostimulatory effects of catecholamine are mediated via the inhibition of adenylate cyclase, whereas the direct effects to slow the heart rate (HR) and to prolong impulse propagation through the AV node are due in great part to activation of I.sub.KAdo. (B. Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 and J. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997) P 2-10). Both, the anti-.beta.-adrenergic action and direct depressant effects on SA and AV nodal function are mediated by the A.sub.1 receptor; there is no role for the A.sub.2A receptor in this response to adenosine. A.sub.2A receptors mediate the coronary vasodilatation caused by adenosine. Stimulation of the A.sub.1 adenosine receptor accordingly shortens the duration and decreases the amplitude of the action potential of AV nodal cells, and hence prolongs the refractory period of the AV nodal cell. The consequence of these effects is to limit the number of impulses conducted from the atria to the ventricles. This forms the basis of the clinical utility of A.sub.1 receptor agonists for the treatment of supraventricular tachycardias, including termination of nodal re-entrant tachycardias, and control of ventricular rate during atrial fibrillation and flutter.
A clinical utility of A.sub.1 agonists therefore is in the treatment of acute and chronic disorders of heart rhythm, especially those diseases characterized by rapid heart rate where the rate is driven by abnormalities in the sinoatrial, atria, and AV nodal tissues. Such disorders include but are not limited to atrial fibrillation, supraventricular tachycardia and atrial flutter. Exposure to A.sub.1 agonists causes a reduction in the heart rate and a regularization of the abnormal rhythm thereby improving cardiovascular function.
A.sub.1 agonists, through their ability to inhibit the effects of catecholamines, decrease cellular cAMP, and thus, should have beneficial effects in the failing heart where increased sympathetic tone increases cellular cAMP levels. The latter has been shown to be associated with increased likelihood of ventricular arrhythmias and sudden death. A.sub.1 l of the above concepts are discussed in reviews regarding the effects of adenosine on cardiac electrophysiology (see B. Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 and J. C. Shryock and L. Belardinelli, Am. J. Cardiology, Vol. 79 (1997) P 2-10).
A controversial area in the field of A.sub.1 adenosine agonism is that the benefit of preconditioning of the heart prior to ischemia may be due to binding of adenosine to the A.sub.1 receptor. Evidence for this hypothesis comes from a rabbit ischemia model wherein 2-chloro-N6-cyclopentyladenosine (CCPA) and R-PIA were administered prior to ischemia providing protection with respect to infarct size (J. D. Thornton et al. Circulation Vol. 85 (1992) 659-665).
A.sub.1 agonists, as a result of their inhibitory action on cyclic AMP generation, have antilipolytic effects in adipocytes that leads to a decreased release of nonesterified fatty acids (NEFA) (E. A. van Schaick et al J. Pharmacokinetics and Biopharmaceutics, Vol. 25 (1997) p 673-694 and P. Strong Clinical Science Vol. 84 (1993) p. 663-669). Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by an insulin resistance that results in hyperglycemia. Factors contributing to the observed hyperglycemia are a lack of normal glucose uptake and activation of skeletal muscle glycogen synthase (GS). Elevated levels of NEFA have been shown to inhibit insulin-stimulated glucose uptake and glycogen synthesis ( D. Thiebaud et al Metab. Clin. Exp. Vol. 31 (1982) p 1128-1136 and G. Boden et al J. Clin. Invest. Vol. 93 (1994) p 2438-2446). The hypothesis of a glucose fatty acid cycle was proposed by P. J. Randle as early as 1963 (P. J. Randle et al Lancet (1963) p. 785-789). A tenet of this hypothesis would be that limiting the supply of fatty acids to the peripheral tissues should promote carbohydrate utilization (P. Strong et al Clinical Science Vol. 84 (1993) p. 663-669).
The benefit of an A.sub.1 agonist in central nervous disorders has been reviewed and the content are included herein by reference (L. J. S. Knutsen and T. F. Murray In Purinergic Approaches in Experimental Therapeutics, Eds. K. A. Jacobson and M. F. Jarvis (1997) Wiley-Liss, N.Y., P -423-470). Briefly, based on experimental models of epilepsy, a mixed A.sub.2A : A.sub.1 agonist, metrifudil, has been shown to be a potent anticonvulsant against seizures induced by the inverse benzodiazepine agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM, H. Klitgaard Eur. J. Pharmacol. (1993) Vol. 224 p. 221-228). In other studies using CGS 21680, an A.sub.2A agonist, it was concluded that the anticonvulsant activity was attributed to activation of the A.sub.1 receptor (G. Zhang et al. Eur. J. Pharmacol. Vol. 255 (1994) p. 239-243). Furthermore, A.sub.1 adenosine selective agonists have been shown to have anticonvulsant activity in the DMCM model (L. J. S. Knutsen In Adenosine and Adenne Nucleotides: From Molecular Biology to Integrative Physiology; eds. L. Belardinelli and A. Pelleg, Kluwer: Boston, 1995, pp 479-487). A second area where an A.sub.1 adenosine agonist has a benefit is in animal models of forebrain ishemia as demonstrated by Knutsen et al (J. Med. Chem. Vol. 42 (1999) p. 3463-3477). The benefit in neuroprotection is believed to be in part due to the inhibition of the release of excitatory amino acids (ibid).
There are a number of full A.sub.1 agonists disclosed in the prior art. However, the agonists disclosed are generally in the forms that are not useful in the mammalian body. Because useful forms of A.sub.1 agonists may not always be stable, soluble or they may have other properties that make their incorporation into therapeutic dosage forms difficult, it is often necessary to identify compositions that are more easily incorporated into therapeutic dosage forms in order to provide the desired therapeutic effect. A.sub.1 so, these agonists fail as useful therapeutics due to side effects caused by the non-selective stimulation of the A.sub.1 adenosine receptor in all biologically available tissues and the desensitization of the desired response preempting their use as chronic agents. Therefore, there remains a need for specific and selective A.sub.1 agonists, precursors and/or pro-drugs that are converted in the body into useful therapeutic compositions.